In hormone replacement therapy (HRT), sometimes also referred to as estrogen replacement therapy, estrogens are administered to prevent or treat symptoms resulting from estrogen deficiency or hypoestrogenism. Hypoestrogenism can occur in both females and males, and can lead to disorders and ailments such as osteoporosis (loss of bone mass), arteriosclerosis, climacteric symptoms such as hot flushes (flashes), sweats, urogenital atrophy, mood disturbances, insomnia, palpitations. Estrogen deficiency has also been associated with cognitive disturbances and Alzheimer's disease.
Hypoestrogenism, and in particular chronic hypoestrogenism, is frequently observed in (peri-)menopausal and post-menopausal women. However, it can also result from hypogonadism or castration, as well as from primary ovarian failure, treatment of e.g. breast cancer with aromatase inhibitor and gonadotropin-releasing hormone analogue treatment of benign gynaecological diseases such as endometriosis, adenomyosis, uterine fibroids (leiomyomas), dysmenorrhoea, menorrhagia and metrorrhagia.
HRT employs continuous administration of effective amounts of an estrogen for prolonged periods of time. The administration of estrogens has been associated, however, with endometrial proliferation in women and it is now widely accepted that “unopposed” estrogen therapy substantially increases the risk of endometrial cancer (Cushing et al., 1998. Obstet. Gynecol. 91, 35-39; Tavani et al., 1999. Drugs Aging, 14, 347-357). There is also evidence of a significant increase in breast cancer with long-term (10-15 years) use of estrogen therapy (Tavani et al., 1999. Drugs Aging, 14, 347-357; Pike et al., 2000. Steroids, 65, 659-664).
In order to counteract the negative effects of unopposed estrogen therapy, adjunctive progestogen treatment is nowadays commonly applied. Regular progestogen administration is believed to inhibit the continual estrogen stimulation of the endometrium through an anti-proliferative effect and appears to reduce the incidence of endometrial carcinoma in post-menopausal women receiving estrogen replacement therapy (Beral et al., 1999. J. Epidemiol. Biostat., 4, 191-210). Such an adjunctive treatment, generally using synthetic progestogens, is given either in continuous combined regimens with estrogen, or added sequentially, typically for about 14 days each month, to continuous estrogen treatment.
Endogenous and exogenous estrogens fulfil important central nervous and metabolic functions in the female organism: normal estrogen levels make a decisive contribution to a woman's well-being. Notwithstanding the widespread use of estrogens in HRT methods, there are still some unsolved problems. Known estrogens, in particular the biogenic estrogens (i.e. estrogens naturally occurring in the human body), show serious pharmacokinetic deficits. Biogenic estrogens such as estradiol, estrone, estrone sulphate, esters of estradiol and estriol become bioavailable only to a very low degree when taken orally. This degree may vary so much from person to person that general dosage recommendations cannot be given. Fast elimination of these estrogens from the blood is another related problem. For instance, for the main human biogenic estrogen 17β-estradiol the half-life is around 1 hour. As a result, between separate (daily) administration events, blood serum levels of such biogenic estrogens tend to fluctuate considerably. Thus, shortly after administration the serum concentration is usually several times higher than the optimum concentration. In addition, if the next administration event is delayed, serum concentrations will quickly decrease to a level where the estrogen is no longer physiologically active.
The most important synthetically altered estrogenic steroid is 17α-ethinyl estradiol (EE). This estrogen is hardly used in HRT methods because prolonged administration of EE has been associated with an increased risk of thromboembolism, which is deemed to be particularly detrimental in menopausal and post-menopausal females. Apart from EE, mestranol has been used in a few cases; mestranol is a “prodrug” that is metabolised to EE in the organism. When applied orally to humans, EE has a much better bioavailability than the biogenic estrogens mentioned above, but its oral bioavailability varies to a large extent from individual to individual. Several authors have pointed to this as well as to the fact that concentrations in the blood proved to be highly fluctuating after oral application of this substance.
In addition to pharmacokinetic problems, the known estrogens also show pharmacodynamic deficits. After resorption from the intestinal lumen, orally applied active ingredients enter the organism via the liver. This fact is of specific importance for estrogenic agents as the liver is a target organ for estrogens; oral intake of estrogens results in strong estrogenic effects in the liver. The secretion activity that is controlled by estrogens in the human liver includes increased synthesis of transport proteins CBG, SHBG, TBG, several factors that are important for the physiology of blood clotting, and lipoproteins. If biogenic estrogens are introduced to the female organism while avoiding passage through the liver (e.g. by transdermal application), the liver functions mentioned remain largely unchanged. Therapeutically equivalent doses of biogenic estrogens, when applied orally, result in clear responses of hepatic parameters, such as increase of SHBG, CBG, angiotensinogen and HDL (high density lipoprotein). These hepatic effects of estrogens are also observed when equine estrogen formulations (so-called conjugated estrogens) are used. Ethinyl estradiol and diethylstilbestrol (DES) have an even greater hepatic estrogenicity. Elger et al., J. Steroid Biochem. Molec. Biol. (1995), 55(3/4), 395-403, have reported that EE or DES have much higher hepato-cellular than systemic estrogenicity: in relation to FSH-secretion inhibitory activity these estrogens are 4-18 times more active in the liver than estrone sulfate.
The aforementioned deficits are of considerable clinical significance when commonly known biogenic and synthetic estrogens are applied. Consequently, there is an as yet unmet need for estrogens that do not display these deficits and which can suitably be administered orally in HRT methods to effectively replace endogenous ovarian secretion of estradiol, i.e. to treat or prevent symptoms of hypoestrogenism.